Yokukansan Alleviates Cancer Pain by Suppressing Matrix Metalloproteinase-9 in a Mouse Bone Metastasis Model

Abstract

Bone cancer pain control is difficult because it includes various characteristics of pain such as nociceptic and neuropathic pain. In this study, we investigated the effect of yokukansan (YKS), one of the traditional Japanese herbal medicines, on cancer pain in mouse bone metastasis model. Oral administration of YKS significantly alleviated pain behavior measured by quantitative body weight bearing. Furthermore, the pain behavior was also significantly alleviated by intrathecal and intraperitoneal administration of matrix metalloproteinase- (MMP-) 9 inhibitor, but not of MMP-2 inhibitor. MMP-9 expression was significantly elevated in the bone tissue on day 3 after carcinoma cell injection and in the ipsilateral spinal cord on day 7, which was suppressed by YKS administration. Taken together, these results suggest that YKS alleviates cancer pain via suppressing MMP-9 expression in bone metastasis model in mice.

The Serotonin-Mediated Anti-Allodynic Effect of Yokukansan on Paclitaxel-Induced Neuropathic Pain

“…Recent studies of YKS for neuropathic pain confirm that YKS relieves mechanical allodynia in partial sciatic nerve ligation mice by regulating the expression of interleukin-6 in astrocytes and/or microglia in the spinal cord [ 24 ] and that YKS has anti-allodynic effects in rats with chronic contraction injuries, which are associated with the blockade of glutamatergic neurotransmission via the activation of glutamate transporters in the spinal cord [ 25 ]. Nakao et al have shown that YKS alleviates cancer pain via suppressing matrix metalloproteinase-9 expression in the bone metastasis model in mice [ 35 ]. The present data show for the first time that YKS affects PTX-induced peripheral neuropathy instead of physical peripheral neuropathy.…”

Analgesic Effect of Combined Therapy with the Japanese Herbal Medicine “Yokukansan” and Electroacupuncture in Rats with Acute Inflammatory Pain

“…Several reports show that YKS is clinically effective against various chronic pain diseases [ 19 , 46 ], and some basic studies have been reported on its mechanisms of action [ 20 , 21 , 47 ]. The activation of N-methyl- d -aspartic acid (NMDA) receptor, a glutamate receptor, is considered a central sensitization [ 48 ].…”

“…There are some reports that the behavioral and psychological symptoms in patients with dementia improved due to YKS use [ 7 , 17 , 18 ]. Recent clinical investigations and preclinical basic studies indicated that YSK could have an analgesic effect on neuropathic pain [ 19 , 20 , 21 ]. However, only a few reports have verified the analgesic effect of YKS on acute pain, and the analgesic effect of combined treatments with other traditional medicines have rarely been verified.…”

Kampo Formulae for the Treatment of Neuropathic Pain ∼ Especially the Mechanism of Action of Yokukansan ∼

“…The analgesic effect of YKS has been proven in some animal models, including a chronic constriction injury (CCI) model ( Suzuki et al, 2012 ; Suga et al, 2015 ), partial sciatic nerve ligation (PSL) model ( Ebisawa et al, 2015 ), bone metastasis model ( Nakao et al, 2019 ), and adjuvant arthritis model ( Honda et al, 2013 ). Several factors are involved in the complex development and promotion of neuropathic pain.…”